An important step toward better understanding neural circuit function was recently made possible thanks to the breakthrough development of optogenetic tools. In this approach, the microbial opsin genes [most notable, Channelrhodopsin (ChR-2) and halorhodopsin (NpHR)] are expressed in neurons either by viral transduction or transgenesis. Neurons expressing opsin can then be activated or inhibited by light at specific wavelengths. Due to its great spatiotemporal resolution, optogenetics is able to functionally dissect brain circuits, as well as to offer new insights into the causal relationship between brain activity and behavior and, possibly, lead to therapies for neuropsychiatric diseases. However, due to the limited tissue penetration of light at the wavelengths necessary to activate optogenetic constructs, the stimulation of behaving animals has to rely on chronically implanted, fiber-optics or mounted LEDs to deliver light into deep brain tissues. Although this method is very useful and has yielded a wealth of information about brain circuits, stimulation via fiber-optics also has important limitations, particularly in regard to chronic stimulation in awake animals. To address this challenging issue, we propose to develop a wireless optogenetic strategy to remotely activate opsins in vivo using a relay nano- illuminator. This approach is buil upon key technologic advances recently made in our laboratory in lanthanide-doped upconversion nanoparticles (UCNPs), a new generation of nanoparticles with unexpected properties. The most significant advantage of UCNPs is their unnatural inverse excitation and emission profiles; i.e., they are excited using biocompatible, low power, deep tissue-penetrant, near infrared radiation that is effectively converted to a higher energy output emission at various shorter wavelengths, including visible light for activation of opsins. We propose two specific aims. For Aim 1, we will characterize the ability of UNCPs to act as relay illuminators in vitro and in vivo. We will initially focus on the first generation of UCNP nanoparticles (CaF2 coated core/shell UCNP) that our preliminary experiments have demonstrated to exhibit robust emission from deep brain tissue. In Aim2, we will develop novel combinatorial synthesis to enhance optogenetic performance of lanthanide-doped UCNPs. This new strategy will overcome many of the limitations of current fiber-optic based approaches, and will enable new applications in both fundamental science and human health.